US4870072A - 2-oxo-1-substituted pyrazolo[1,5-A]pyrimidine-6-carboxylic acid esters as blood pressure reducing agents - Google Patents

2-oxo-1-substituted pyrazolo[1,5-A]pyrimidine-6-carboxylic acid esters as blood pressure reducing agents Download PDF

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US4870072A
US4870072A US07/145,007 US14500788A US4870072A US 4870072 A US4870072 A US 4870072A US 14500788 A US14500788 A US 14500788A US 4870072 A US4870072 A US 4870072A
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alkyl
aryl
cycloalkyl
piperazinyl
halo
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Karnail Atwal
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ER Squibb and Sons LLC
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ER Squibb and Sons LLC
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Priority to EP19890901760 priority patent/EP0380592A4/en
Priority to PCT/US1989/000047 priority patent/WO1989006535A1/en
Assigned to E.R. SQUIBB & SONS, INC., A CORP OF DE reassignment E.R. SQUIBB & SONS, INC., A CORP OF DE ASSIGNMENT OF ASSIGNORS INTEREST. Assignors: ATWAL, KARNAIL
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • R 1 is ##STR5## or ##STR6##
  • R 2 is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, --(CH 2 ) n -Y 1 , or halo substituted alkyl;
  • R 3 is hydrogen, alkyl, cycloalkyl, aryl, --(CH 2 ) n --Y 2 , --(CH 2 ) p --Y 3 , or halo substituted alkyl;
  • R 4 is aryl
  • R 5 is hydrogen, alkyl, cycloalkyl, aryl, or arylalkyl and R 6 is hydrogen, alkyl, cycloalkyl, --(CH 2 ) n --Y 2 , --(CH 2 ) p --Y 3 or halo substituted alkyl, or R 5 and R 6 taken together with the nitrogen atom to which they are attached are 1-pyrrolidinyl, 1-piperidinyl, 1-azepinyl, 4-morpholinyl, 4-thiamorpholinyl, 1-piperizinyl, 4-alkyl-1-piperazinyl, 4-arylalkyl-1-piperazinyl, 4-diarylalkyl-1-piperazinyl or 1-pyrrolidinyl, 1-piperidinyl, or 1-azeipinyl substituted with alkyl, alkoxy, alkylthio, halo, trifluoromethyl or hydroxy;
  • R 7 is alkyl, cycloalkyl, aryl, --(CH 2 ) n --Y 2 , --(CH 2 ) p --Y 3 or halo substituted alkyl;
  • Y 1 is cycloalkyl, aryl, hydroxyl, alkoxy, aryl--(CH 2 ) m --O--, mercapto, alkylthio, aryl--(CH 2 ) m --S--, amino, substituted amino, carbamoyl, (substituted amino) ##STR7## carboxyl, alkoxycarbonyl, ##STR8## or ##STR9##
  • Y 2 is cycloalkyl, aryl, carbamoyl, ##STR10## carboxyl, alkoxycarbonyl, ##STR11## or ##STR12##
  • Y 3 is hydroxyl, alkoxy, aryl--(CH 2 ) m --O--, mercapto, alkylthio, aryl--(CH 2 ) m --S--, ##STR13## amino or substituted amino;
  • n is 0 or an integer of 1 to 6;
  • n is an integer of 1 to 6;
  • p is a integer of 2 to 6.
  • alkyl and “alkoxy” refer to both straight and branched chain groups. Those groups having 1 to 8 carbon atoms are preferred.
  • halo substituted alkyl refers to alkyl groups (as described above) in which one or more hydrogens have been replaced by chloro, bromo or fluoro groups.
  • exemplary groups are trifluoromethyl, which is preferred, pentafluoroethyl, 2,2,2-trichloroethyl, chloromethyl, bromomethyl, etc.
  • aryl refers to phenyl and substituted phenyl.
  • exemplary substituted phenyl groups are phenyl groups substituted with one, two or three alkyl, alkoxy, alkylthio, halo, nitro cyano, trifluoromethyl, or difluoromethoxy groups.
  • alkenyl and alkynyl refer to both straight and branched chain groups. Those groups having 2 to 8 carbon atoms are preferred.
  • cycloalkyl refers to those groups having 3, 4, 5, 6 or 7 carbon atoms.
  • halo refers to chloro, bromo, fluoro and iodo.
  • substituted amino refers to a group of the formula --NZ 1 Z 2 wherein Z 1 is hydrogen, alkyl, or aryl--(CH 2 ) m -- and Z 2 is alkyl or aryl--(CH 2 ) m -- or Z 1 and Z 2 taken together with the nitrogen atom to which they are attached are 1-pyrrolidinyl, 1-piperidinyl, 1-azepinyl, 4-morpholinyl, 4-thiamorpholinyl, 1-piperazinyl, 4-alkyl-1-piperazinyl, 4-arylalkyl-1-piperazinyl, 4-diarylalkyl-1-piperazinyl, or 1-pyrrolidinyl, 1-piperidinyl, or 1-azepinyl substituted with alkyl, alkoxy, alkylthio, halo, trifluoromethyl or hydroxy.
  • the compounds of formula I, and the pharmaceutically acceptable salts thereof, are cardiovascular agents. They act as calcium entry blocking vasodilators and are especially useful as hypotensive agents.
  • a composition containing one (or a combination) of the compounds of this invention the blood pressure of a hypertensive mammalian (e.g., human) host is reduced.
  • the substance is preferably administered orally, but parenteral routes such as the subcutaneous, intramuscular or intravenous routes can also be employed.
  • hypotensive agents in addition to being hypotensive agents may also be useful as anti-arrhythmic agents, anti-anginal agents, anti-fibrillatory agents, anti-asthmatic agents, anti-ischemic agents, and in limiting myocardial infarction.
  • the compounds of this invention can also be formulated in combination with a diuretic, or a beta-adrenergic agent, or angiotensin converting enzyme inhibitor.
  • Suitable diuretics include the thiazide diuretics such as hydrochlorothiazide and bendroflumethiazide, suitable beta-adrenergic agents include nadolol, and suitable angiotensin converting enzyme inhibitors include captopril.
  • the compounds of formula I can be formulated for use in the reduction of blood pressure in compositions such as tablets, capsules or elixirs for oral administration, or in sterile solutions or suspensions for parenteral administration.
  • compositions such as tablets, capsules or elixirs for oral administration, or in sterile solutions or suspensions for parenteral administration.
  • About 10 to 500 milligrams of a compound of formula I is compounded with physiologically acceptable vehicle, carrier, excipient, binder, preservative, stabilizer, flavor, etc., in a unit dosage form as called for by accepted pharmaceutical practice.
  • the amount of active substance in these compositions or preparations is such that a suitable dosage in the range indicated is obtained.
  • a compound of the formula ##STR14## that is, 3-amino-5-pyrazolone is reacted with a keto ester having the formula ##STR15## to provide a compound of the formula ##STR16##
  • the reaction is preferably heated in the presence of an organic solvent, such as dimethylformamide.
  • the compound of formula IV can be treated with phosgene or 4-nitrophenylchloroformate followed by an amine of the formula R 5 R 6 NH.
  • the reaction is preferably run in the presence of an organic base, such as pyridine, and triethylamine.
  • the compounds of formula I that contain a basic or acid group form acid addition and basic salts with a variety of inorganic and organic acids and bases.
  • the pharmaceutically acceptable salts are preferred, although other salts may also be useful in isolating or purifying the product.
  • Such pharmaceutically acceptable acid addition salts include those formed with hydrochloric acid, methanesulfonic acid, toluenesulfonic acid, sulfuric acid, acetic acid, maleic acid, etc.
  • Pharmaceutically acceptable basic salts include alkali metal salts (e.g. sodium, potassium and lithium) and alkaline earth metal salts (e.g. calcium and magnesium). The salts can be obtained by reacting the product with an equivalent amount of the acid in a medium in which the salt precipitates.
  • Preferred compounds of this invention are those wherein:
  • R 1 is ##STR21## or ##STR22##
  • R 2 is alkyl (especially methyl), R 3 is alkyl and R 4 is substituted phenyl.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Cardiovascular activity is exhibited by compounds having the formula ##STR1## or a pharmaceutically acceptable salt thereof wherein R1 is ##STR2## or ##STR3## and R2, R3 and R4 are as defined herein.

Description

BRIEF DESCRIPTION OF THE INVENTION
Compounds having the formula ##STR4## and pharmaceutically acceptable salts thereof, are cardiovascular agents. In formula I, and throughout the specification, the symbols are as defined below.
R1 is ##STR5## or ##STR6##
R2 is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, --(CH2)n -Y1, or halo substituted alkyl;
R3 is hydrogen, alkyl, cycloalkyl, aryl, --(CH2)n --Y2, --(CH2)p --Y3, or halo substituted alkyl;
R4 is aryl;
R5 is hydrogen, alkyl, cycloalkyl, aryl, or arylalkyl and R6 is hydrogen, alkyl, cycloalkyl, --(CH2)n --Y2, --(CH2)p --Y3 or halo substituted alkyl, or R5 and R6 taken together with the nitrogen atom to which they are attached are 1-pyrrolidinyl, 1-piperidinyl, 1-azepinyl, 4-morpholinyl, 4-thiamorpholinyl, 1-piperizinyl, 4-alkyl-1-piperazinyl, 4-arylalkyl-1-piperazinyl, 4-diarylalkyl-1-piperazinyl or 1-pyrrolidinyl, 1-piperidinyl, or 1-azeipinyl substituted with alkyl, alkoxy, alkylthio, halo, trifluoromethyl or hydroxy;
R7 is alkyl, cycloalkyl, aryl, --(CH2)n --Y2, --(CH2)p --Y3 or halo substituted alkyl;
Y1 is cycloalkyl, aryl, hydroxyl, alkoxy, aryl--(CH2)m --O--, mercapto, alkylthio, aryl--(CH2)m --S--, amino, substituted amino, carbamoyl, (substituted amino) ##STR7## carboxyl, alkoxycarbonyl, ##STR8## or ##STR9##
Y2 is cycloalkyl, aryl, carbamoyl, ##STR10## carboxyl, alkoxycarbonyl, ##STR11## or ##STR12##
Y3 is hydroxyl, alkoxy, aryl--(CH2)m --O--, mercapto, alkylthio, aryl--(CH2)m --S--, ##STR13## amino or substituted amino;
m is 0 or an integer of 1 to 6;
n is an integer of 1 to 6; and
p is a integer of 2 to 6.
Listed below are definitions of various terms used to describe the compounds of this invention. These definitions apply to the terms as they are used throughout the specification (unless they are otherwise limited in specific instances) either individually or as part of a larger group.
The terms "alkyl" and "alkoxy" refer to both straight and branched chain groups. Those groups having 1 to 8 carbon atoms are preferred.
The term "halo substituted alkyl" refers to alkyl groups (as described above) in which one or more hydrogens have been replaced by chloro, bromo or fluoro groups. Exemplary groups are trifluoromethyl, which is preferred, pentafluoroethyl, 2,2,2-trichloroethyl, chloromethyl, bromomethyl, etc.
The term "aryl" refers to phenyl and substituted phenyl. Exemplary substituted phenyl groups are phenyl groups substituted with one, two or three alkyl, alkoxy, alkylthio, halo, nitro cyano, trifluoromethyl, or difluoromethoxy groups.
The terms "alkenyl" and "alkynyl" refer to both straight and branched chain groups. Those groups having 2 to 8 carbon atoms are preferred.
The term "cycloalkyl" refers to those groups having 3, 4, 5, 6 or 7 carbon atoms.
The term "halo" refers to chloro, bromo, fluoro and iodo.
The term "substituted amino" refers to a group of the formula --NZ1 Z2 wherein Z1 is hydrogen, alkyl, or aryl--(CH2)m -- and Z2 is alkyl or aryl--(CH2)m -- or Z1 and Z2 taken together with the nitrogen atom to which they are attached are 1-pyrrolidinyl, 1-piperidinyl, 1-azepinyl, 4-morpholinyl, 4-thiamorpholinyl, 1-piperazinyl, 4-alkyl-1-piperazinyl, 4-arylalkyl-1-piperazinyl, 4-diarylalkyl-1-piperazinyl, or 1-pyrrolidinyl, 1-piperidinyl, or 1-azepinyl substituted with alkyl, alkoxy, alkylthio, halo, trifluoromethyl or hydroxy.
DETAILED DESCRIPTION OF THE INVENTION
The compounds of formula I, and the pharmaceutically acceptable salts thereof, are cardiovascular agents. They act as calcium entry blocking vasodilators and are especially useful as hypotensive agents. Thus, by the administration of a composition containing one (or a combination) of the compounds of this invention, the blood pressure of a hypertensive mammalian (e.g., human) host is reduced. A single dose, or two to four divided daily doses, provided on a basis of about 0.1 to 100 milligrams per kilogram of body weight per day, preferably from about 1 to about 50 milligrams per kilogram per day, is appropriate to reduce blood pressure. The substance is preferably administered orally, but parenteral routes such as the subcutaneous, intramuscular or intravenous routes can also be employed.
As a result of the calcium entry blocking activity of the compounds of formula I, and the pharmaceutically acceptable salts thereof, it is believed that such compounds in addition to being hypotensive agents may also be useful as anti-arrhythmic agents, anti-anginal agents, anti-fibrillatory agents, anti-asthmatic agents, anti-ischemic agents, and in limiting myocardial infarction.
The compounds of this invention can also be formulated in combination with a diuretic, or a beta-adrenergic agent, or angiotensin converting enzyme inhibitor. Suitable diuretics include the thiazide diuretics such as hydrochlorothiazide and bendroflumethiazide, suitable beta-adrenergic agents include nadolol, and suitable angiotensin converting enzyme inhibitors include captopril.
The compounds of formula I can be formulated for use in the reduction of blood pressure in compositions such as tablets, capsules or elixirs for oral administration, or in sterile solutions or suspensions for parenteral administration. About 10 to 500 milligrams of a compound of formula I is compounded with physiologically acceptable vehicle, carrier, excipient, binder, preservative, stabilizer, flavor, etc., in a unit dosage form as called for by accepted pharmaceutical practice. The amount of active substance in these compositions or preparations is such that a suitable dosage in the range indicated is obtained.
To prepare the compounds of formula I, a compound of the formula ##STR14## that is, 3-amino-5-pyrazolone, is reacted with a keto ester having the formula ##STR15## to provide a compound of the formula ##STR16## The reaction is preferably heated in the presence of an organic solvent, such as dimethylformamide.
Reaction of compound IV with a compound having the formula
R.sub.5 --N═C═O                                    V
in solvents, such as tetrahydrofuran and pyridine, to provide the compounds of formula I wherein R1 is ##STR17## and R6 is hydrogen.
To prepare the compounds of formula I where R1 is ##STR18## and R6 is other than hydrogen, the compound of formula IV can be treated with phosgene or 4-nitrophenylchloroformate followed by an amine of the formula R5 R6 NH. The reaction is preferably run in the presence of an organic base, such as pyridine, and triethylamine.
To prepare the compounds of formula I where R1 is ##STR19## a compound of formula IV, in a solvent, such as dichloromethane, and an organic base, such as pyridine, is reacted with a compound of the formula ##STR20##
The compounds of formula I that contain a basic or acid group form acid addition and basic salts with a variety of inorganic and organic acids and bases. The pharmaceutically acceptable salts are preferred, although other salts may also be useful in isolating or purifying the product. Such pharmaceutically acceptable acid addition salts include those formed with hydrochloric acid, methanesulfonic acid, toluenesulfonic acid, sulfuric acid, acetic acid, maleic acid, etc. Pharmaceutically acceptable basic salts include alkali metal salts (e.g. sodium, potassium and lithium) and alkaline earth metal salts (e.g. calcium and magnesium). The salts can be obtained by reacting the product with an equivalent amount of the acid in a medium in which the salt precipitates.
Preferred compounds of this invention are those wherein:
R1 is ##STR21## or ##STR22##
R2 is alkyl (especially methyl), R3 is alkyl and R4 is substituted phenyl.
The following examples are specific embodiments of this invention.
EXAMPLE 1 4,7-Dihydro-5-methyl-7-(3-nitrophenyl)-2-oxopyrazolo[1,5-a]pyrimidine-1,6-(2H)dicarboxylic acid, bis(1-methylethyl) ester
A. 1,2,4,7-Tetrahydro-5-methyl-7-(3-nitrophenyl)-2-oxopyrazolo[1,5,-a]pyrimidine-6-carboxylic acid, 1-methylethyl ester
A mixture of 3-amino-5-pyrazolone (3.57 g, 36.1 mmole) and 2-[(3-nitrophenyl)methylene]-3-oxobutanoic acid, 1-methylethyl ester (10 g, 36.1 mmole) in dry dimethylformamide (30 ml) was heated at 70° C. under argon for 24 hours. The reaction mixture was allowed to cool to room temperature and then diluted with ether. The resultant precipitate was filtered off and recrystallized from isopropanol to provide 4.23 g of the title A compound in crystalline form, m.p. 254°-256° C.
Analysis calc'd for C17 H18 N4 O5 : C, 56.98; H, 5.06; N, 15.63; Found: C, 57.18; H, 5.10; N, 15.70.
B. 4,7-Dihydro-5-methyl7(3-nitrophenyl)-2-oxopyrazolo[1,5-a]pyrimidine-1,6(2H)dicarboxylic acid, bis(1-methylethyl) ester
The suspension of the title A compound (1.43 g, 4.0 mmol) in dichloromethane (10 mL) and pyridine (2 mL) was treated at 0° C. under argon with isopropylchloroformate (0.6 mL, 5.2 mmol). After the addition was finished, the cooling bath was removed and the reaction was allowed to stir at room temperature for 1 hour. The resulting solution was diluted with ethyl acetate and was washed wtih 1N hydrochloric acid, water and brine. After drying over anhydrous magnesium sulfate, the solvent was removed and the residue was purified by flash chromatography. The fractions containing the desired product were collected and evaporated. The residue was crystallized from ether-hexanes to yield 370 mg of a colorless solid. This material was combined with another batch of the same product and crystallized from isopropyl ether-dichloromethane to give the title compound as a colorless solid, m.p. 162°-164° C.
Analysis calc'd for C21 H24 N4 O7 : C, 56.75; H, 5.44; N, 12.60; Found: C, 56.92; H, 5.34; N, 12.31.
EXAMPLE 2 1,2,4,7-Tetrahydro-5-methyl-1-[[(1-methylethyl)amino]carbonyl]-7-(3-nitrophenyl)-2-oxopyrazolo-[1,4-a]pyrimidine-6-carboxylic acid, 1-methylethyl ester
The suspension of the title A compound from Example 1 (1.43 g, 4.0 mmol) in tetrahydrofuran (10 mL) and pyridine (1mL) was treated at 0° C. under argon with isopropylisocyanate (0.33 mL, 3.35 mmol). After the addition was finished, the cooling bath was removed and the reaction was allowed to stir at room temperature for 5 hours. The resulting solution was diltued with ethy acetate and was washed with 1N hydrochloric acid, water and brine. After drying over anhydrous magnesium sulfate, the solvent was removed and the residue was crystallized from ether-hexanes to yield 1.04 g of the title compound as a colorless solid, m.p. 172°∝174° C. (sinters at 167° C.).
Analysis calc'd for C21 H25 N5 O6: C, 56.87; H,, 5.68; N, 15.80; Found: C, 57.18; H, 5.66; N, 15.56.
EXAMPLE 3 1,2,4,7-Tetrahydro-5-methyl-7-(3-nitrophenyl)-2-oxo-1-[(propylamino)carbonyl]pyrazolo[1,5-a]pyrimidine-6-carboxylic acid, 1-methylethyl ester
The suspension of the title A compound from Example 1 (0.75 g, 2.0 mmol) in tetrahydrofuran (10 mL) and pyridine (1 mL) was treatetd at 0° C. under argon with n-propylisocyanate (0.24 mL, 2.5 mmol). After the addition was finished, the cooling bath was removed and the reaction was allowed to stir at room temperature for 5 hours. The resulting solution was diluted with ethyl acetate and was washed with 1N hydrochloric acid, water and brine. After drying over anhydrous magnesium sulfate, the solvent was removed and the residue was crystallized from ether-hexanes to yield 701 mg of a colorless solid. The product was recrystallized from dichloromethane-isopropyl ether to yield 601 mg of the title compound, m.p. 160°-163° C.
Analysis calc'd for C21 H25 N5 O6 : C, 56.87; H, 5.69; N, 15.80; Found: C, 56.94; H, 5.62; N, 15.68.
EXAMPLES 4-25
Using the procedures outlined above and in Examples 1-3, the following additional compounds of formula I within the scope of the present invention can be made. ##STR23##
__________________________________________________________________________
Ex.                                                                       
No. R.sub.2    R.sub.3           R.sub.4    R.sub.5       R.sub.6         
__________________________________________________________________________
 4 CH.sub.3    CH.sub.2 CH.sub.3                                          
                                             ##STR24##    H               
 5 CH.sub.3                                                               
                ##STR25##                                                 
                                  ##STR26## CH.sub.3      CH.sub.3        
 ##STR27##                                                                
                ##STR28##                                                 
                                  ##STR29## CH.sub.3 CH.sub.2 CH.sub.2    
                                                          H               
 7 CH.sub.2 CH.sub.2 OCH.sub.3                                            
               CH.sub.2 CH.sub.3                                          
                                  ##STR30## CH.sub.3 CH.sub.2             
                                                          H               
 ##STR31##     CH.sub.2 CH.sub.3                                          
                                  ##STR32## CH.sub.3      H               
 9 CH.sub.2 CH.sub.3                                                      
               CH.sub.2 CH.sub.2 OCH.sub.3                                
                                  ##STR33## CH.sub.2 CH.sub.2 CH.sub.2    
                                            CH.sub.2                      
 ##STR34##     CH.sub.2 CH.sub.3                                          
                                  ##STR35## CH.sub.2 CH.sub.2 SCH.sub.2   
                                            CH.sub.2                      
11 CH.sub.3                                                               
                ##STR36##                                                 
                                  ##STR37##                               
                                             ##STR38##    H               
12 CH.sub.3                                                               
                ##STR39##                                                 
                                  ##STR40## CH.sub.3      CH.sub.2        
                                                          CH.sub.3        
13 CH.sub.2 CH.sub.2 CH.sub.3                                             
               CH.sub.3                                                   
                                  ##STR41##                               
                                             ##STR42##    H               
14 CH.sub.2 CH.sub.3                                                      
                ##STR43##                                                 
                                  ##STR44##                               
                                             ##STR45##                    
__________________________________________________________________________
Ex. No.                                                                   
     R.sub.2        R.sub.3         R.sub.4     R.sub.7                   
__________________________________________________________________________
15   CH.sub.3 CH.sub.2                                                    
                    CH.sub.3                                              
                                     ##STR46##                            
                                                 ##STR47##                
16   CH.sub.3                                                             
                     ##STR48##                                            
                                     ##STR49##                            
                                                 ##STR50##                
17   CH.sub.2 CH.sub.2 OCH.sub.3                                          
                    CH.sub.2 CH.sub.3                                     
                                     ##STR51##  CH.sub.2 CH.sub.3         
18                                                                        
      ##STR52##     CH.sub.2 CH.sub.3                                     
                                     ##STR53##                            
                                                 ##STR54##                
19   CH.sub.2 CH.sub.3                                                    
                     ##STR55##                                            
                                     ##STR56##  CH.sub.2CH.sub.2 CH.sub.3 
                                                5                         
20   CH.sub.3                                                             
                     ##STR57##                                            
                                     ##STR58##  CH.sub.2 CH.sub.3         
21                                                                        
      ##STR59##     CH.sub.2 CH.sub.3                                     
                                     ##STR60##  CH.sub.3                  
22                                                                        
      ##STR61##     CH.sub.3                                              
                                     ##STR62##  CH.sub.2 CH.sub.2         
                                                OCH.sub.3                 
23   CH.sub.3       CH.sub.2 CH.sub.3                                     
                                     ##STR63##                            
                                                 ##STR64##                
24   CH.sub.3                                                             
                     ##STR65##                                            
                                     ##STR66##  CH.sub.3                  
25   CH.sub.3       CH.sub.2 CH.sub.2 CH.sub.3                            
                                     ##STR67##  CH.sub.2 CH.sub.2         
__________________________________________________________________________
                                                CH.sub.3

Claims (9)

What is claimed is:
1. Compounds having the formula ##STR68## or a pharmaceutically acceptable salt thereof wherein R1 is ##STR69## or ##STR70## R2 is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, --(CH2)n --Y1, or halo substituted alkyl;
R3 is hydrogen, alkyl, cycloalkyl, aryl, --(CH2)n --Y2, --(CH2)p --Y3, or halo substituted alkyl;
R4 is aryl;
R5 is hydrogen, alkyl, cycloalkyl, aryl, or arylalkyl and R6 is hydrogen, alkyl, cycloalkyl, --(CH2)n --Y2, --(CH2)p --Y3 or halo substituted alkyl, or R5 and R6 taken together with the nitrogen atom to which they are attached are 1-pyrrolidinyl, 1-piperidinyl, 1-azepinyl, 4-morpholinyl, 4-thiamorpholinyl, 1-piperazinyl, 4-alkyl-1-piperazinyl, 4-arylalkyl-1-piperazinyl, 4-diarylalkyl-1-piperazinyl or 1-pyrrolidinyl, 1-piperidinyl, or 1-azeipinyl substituted with alkyl, alkoxy, alkylthio, halo, trifluoromethyl or hydroxy;
R7 is alkyl, cycloalkyl, aryl, --(CH2)n --Y2, --(CH2)p --Y3 or halo substituted alkyl;
Y1 is cycloalkyl, aryl, hydroxyl, alkoxy, aryl--(CH2)m --O--, mercapto, alkylthio, aryl--(CH2)m --S--, amino, substitued amino, carbamoyl, ##STR71## carboxyl, alkoxycarbonyl, ##STR72## ##STR73## Y2 is cycloalkyl, aryl, carbamoyl, ##STR74## carboxyl, alkoxycarbonyl, ##STR75## Y3 is hydroxyl, alkoxy, aryl--(CH2)m --O--, mercapto, alkylthio, aryl--(CH2)m --S--, ##STR76## amino or substituted amino; m is 0 or an integer of 1 to 6;
n is an integer of 1 to 6; and
p is an integer of 2 to 6;
"alkyl" and "alkoxy" refer to both straight and branched chain groups having 1 to 8 carbon atoms;
"halo substituted alkyl" refers to alkyl groups in which one or more hydrogens have been replaced by chloro, bromo or fluoro groups;
"aryl" refers to phenyl and substituted phenyl wherein the substituents are independently selected from one, two or three alkyl, alkoxy, alkylthio, halo, nitro cyano, trifluoromethyl, or difluoromethoxy groups;
"alkenyl" and "alkynyl" refer to both straight and branched chaing roups having 2 to 8 carbon atoms;
"cycloalkyl" refers to those groups having 3, 4, 5, 6 or 7 carbon atoms;
"halo" refers to chloro, bromo, fluoro and iodo; and,
"substituted amino" refers to a group of the formula --NZ1 Z2 wherein Z1 is hydrogen, alkyl, or aryl--(CH2)m -- and Z2 is alkyl or aryl--(CH2)m -- or Z1 and Z2 taken together with the nitrogen atom to which they are attached are 1-pyrrolidinyl, 1-piperidinyl, 1-azepinyl, 4-morpholinyl, 4-thiamorpholinyl, 1-piperazinyl, 4-alkyl-1-piperazinyl, 4-arylalkyl-1-piperazinyl, 4-diarylalkyl-1-piperazinyl, or 1-pyrrolidinyl, 1-piperidinyl, or 1-azepinyl substituted with alkyl, alkoxy, alkylthio, halo, trifluoromethyl or hydroxy.
2. A compound in accordance with claim 1 wherein
R1 is ##STR77## R2 is alkyl; R3 is alkyl; and,
R4 is substituted phenyl.
3. A compound in accordance with claim 1 wherein ##STR78## R2 is methyl; R3 is isopropyl; and,
R4 is 3-nitrophenyl.
4. A compound in accordance with claim 1 wherein ##STR79## R2 is methyl; R3 is isopropyl; and,
R4 is 3-nitrophenyl.
5. A compound in accordance with claim 1 wherein
R1 is ##STR80## R2 is methyl; R3 is isopropyl; and,
R4 is 3-nitrophenyl.
6. A compound in accordance with claim 1 having the name 4,7-dihydro-5-methyl-7-(3-nitrophenyl)-2-oxopyrazolo[1,5-a]pyrimidine-1,6(2H)dicarboxylic acid, bis(1-methylethyl) ester.
7. A compound in accordance with claim 1 having the name 1,2,4,7-tetrahydro-5-methyl-1-[[(1-methylethyl)amino]carbonyl]-7-(3-nitrophenyl)-2-oxopyrazolo-[1,4-a]pyrimidine-6-carboxylic acid, 1-methylethyl ester.
8. A compound in accordance with claim 1 having the name 1,2,4,7-tetrahydro-5-methyl-7-(3-nitrophenyl)-2-oxo-1-[(propylamino)carbonyl]pyrazolo[1,5-a]pyrimidine-6-carboxylic acid, 1-methylethyl ester.
9. A method for reducing the blood pressure of a mammalian host in need thereof which comprises administering to said host an effective amount of a compound having the formula ##STR81## or a pharmaceutically acceptable salt thereof wherein R1 is ##STR82## or ##STR83## R2 is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, --(CH2)n --Y1, or halo substituted alkyl;
R3 is hydrogen, alkyl, cycloalkyl, aryl, --(CH2)n --Y2, --(CH2)p --Y3, or halo substituted alkyl;
R4 is aryl;
R5 is hydrogen, alkyl, cycloalkyl, aryl, or arylalkyl and R6 is hydrogen, alkyl, cycloalkyl, --(CH2)n --Y2, --(CH2)p --Y3 or halo substituted alkyl, or R5 and R6 taken together with the nitrogen atom to which they are attached are 1-pyrrolidinyl, 1-piperidinyl, 1-azepinyl, 4-morpholinyl, 4-thiamorpholinyl, 1-piperazinyl, 4-alkyl-1-piperazinyl, 4-arylalkyl-1-piperazinyl, 4-diarylalkyl-1-piperazinyl or 1-pyrrolidinyl, 1-piperidinyl, or 1-azeipinyl substituted with alkyl, alkoxy, alkylthio, halo, trifluoromethyl or hydroxy;
R7 is alkyl, cycloalkyl, aryl, --(CH2)n --Y2, --(CH2)p --Y3 or halo substituted alkyl;
Y1 is cycloalkyl, aryl, hydroxyl, alkoxy, aryl--(CH2)m --O--, mercapto, alkylthio, aryl--(CH2)m --S--, amino, substituted amino, carbamoyl, ##STR84## carboxyl, alkoxycarbonyl, ##STR85## ##STR86## Y2 is cycloalkyl, aryl, carbamoyl, ##STR87## carboxyl, alkoxycarbonyl, ##STR88## Y3 is hydroxy, alkoxy, aryl--(CH2)m --O--, mercapto, alkylthio, aryl--(CH2)m --S--, ##STR89## ##STR90## amino or substituted amino; m is 0 or an integer of 1 to 6;
n is an integer of 1 to 6; and
p is an integer of 2 to 6;
"alkyl" and "alkoxy" refer to both straight and branched chain groups having 1 to 8 carbon atoms;
"halo substituted alkyl" refers to alkyl groups in which one ore more hydrogens have been replaced by chloro, bromo or fluoro groups;
"aryl" refers to phenyl and substituted phenyl wherein the substituents are independently selected from one, two or three alkyl, alkoxy, alkylthio, halo, nitro cyano, trifluoromethyl, or difluoromethoxy groups;
"alkenyl" and "alkynyl" refer to both straight and branched chain groups having 2 to 8 carbon atoms;
"cycloalkyl" refers to those groups having 3, 4, 5, 6 or 7 carbon atoms;
"halo" refers to chloro, bromo, fluoro and iodo; and,
"substituted amino" refers to a group of the formula --NZ1 Z2 wherein Z1 is hydrogen, alkyl, or aryl--(CH2)m -- and Z2 is alkyl or aryl--(CH2)m -- or Z1 and Z2 taken together with the nitrogen atom to which they are attached are 1-pyrrolidinyl, 1-piperdinyl, 1-azepinyl, 4-morpholinyl, 4-thiamorpholinyl, 1-piperazinyl, 4-alkyl-1-piperazinyl, 4-arylalkyl-1-piperazinyl, 4-diarylalkyl-1-piperazinyl, or 1-pyrrolidinyl, 1-piperidinyl, or 1-azepinyl substituted with alkyl, alkoxy, alkylthio, halo, trifluoromethyl or hydroxy.
US07/145,007 1988-01-19 1988-01-19 2-oxo-1-substituted pyrazolo[1,5-A]pyrimidine-6-carboxylic acid esters as blood pressure reducing agents Expired - Lifetime US4870072A (en)

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EP19890901760 EP0380592A4 (en) 1988-01-19 1989-01-05 2-oxo-1-substituted pyrazolo 1,5-a¨pyrimidine-6-carboxylic acid esters
PCT/US1989/000047 WO1989006535A1 (en) 1988-01-19 1989-01-05 2-OXO-1-SUBSTITUTED PYRAZOLO[1,5-a]PYRIMIDINE-6-CARBOXYLIC ACID ESTERS

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GB599891A (en) * 1944-11-17 1948-03-23 Gen Aniline & Film Corp 1-substituted-2,5-diketo-7-methyl-pyrimido-pyrazoles and process of preparing the same
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